Pyridine bis(dithiocarbamate)derivatives and preparation thereof

ABSTRACT

PYRIDINE BIS(DITHIOCARBAMATE) DERIVATIVES HAVING THE FORMULA:   2,6-BIS(R1-N(-R2)-C(=S)-S-CH2-)PYRIDINE   WHEREIN R1 REPRESENTS A LOWER ALKYL GROUP OR A LOWER ALKENE GROUP OR A PHENYL GROUP AND R2 REPRESENTS A HYDROGEN ATOM OR A LOWER ALKYL GROUP, OR R1 AND R2 TAKEN TOGETHER MAY FORM A HETEROCYCLIC RING WITH THE NITROGEN ATOM, HAS BEEN PREPARED BY REACTING 2,6-BIS(HALOMETHYL) PYRIDINE WITH A METAL SALT OR AMINE SALT OR DITHIOCARBAMIC ACID HAVING THE FORMULA: OR WITH CARBON BISULFIDE AND AN AMINE HAVING THE FORMULA: THESE PYRIDINE BIS(DITHIOCARBAMATE) DERIVATIVES EXHIBIT PHYSIOLOGICAL EFFECTS ON THE CIRCULATORY STSTEM AND DEMONSTRATE ANDT-HYPERTENSIVE AND ANTI-INFLAMMATORY PROPERTIES.   R1NCS   OR WITH CARBON 2,6-BISULFIDE AND AN AMINE HAVING THE FORMULA: ISOTHIOCYANATE OF THE FORMULA:   R1R2NH       R1-N(-R2)-C(=S)-SH

United States Patent 3,810,900 PYRIDINE BIS(DITH[0CARBAMATE) DERIVA-TIVES AND PREPARATION THEREOF Ikuo Matsumoto, Kanji Nakagawa, MeikiMatsuzaki, and Kenji Horiuchi, Tokyo, Japan, assignors to BanyuPharmaceutical Co., Ltd., and Hiroyoshi Hidaka, Tokyo, Japan No Drawing.Filed May 19, 1972, Ser. No. 254,943 Claims priority, application Japan,May 25, 1971,

Int. 01. com 29/10, 31/50 Us. c1. zen-293.69 2 Claims ABSTRACT THEDISCLOSURE Pyridine bis(dithiocarbamate) derivatives having the formula:1

1 I R R NESCH N CHZSC INR R.

These pyridine bis(d ithiocarbamate) derivatives exhibit physiologicaleffects on the circulatory system and demon- Patented May 14, 1974DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Pyridinebis(dithiocarbamate) derivatives having the formula:

7 u -R1R1NCSCHQ' L CHzSCNNR wherein R represents a lower alkyl group ora lower alkene group or a phenyl 'groupand R representsa by strateanti-hypertensive and anti-inflammatory properties. H

11-..BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to. pyridine bis(dithiocarbamate)' derivatives and to a methodfor preparing same, which are useful as agents having physiologicalactivity and can be used for the treatment of disorders of thecirculatory sys l tem and particularly for the treatment 0 hypertension.These derivatives have also been found to be useful for the treatment ofmental disease, particularly schizoprhenia.

SUMMARY OF THE INVENTION Accordingly, it is one object of this inventionto provide a process for preparing pyridine bis(dithiocarbamate)derivatives which are useful for the treatment of mental disorders andfor circulatory disorders.

This and other objects, as will hereinafter become more readilyapparent, have been attained by the provision drogen atom or a loweralkyl group, or R and R taken together may form a heterocyclicring withthe nitrogen atom, can be prepared by several producers.

1) They can be prepared by reacting 2,6-bis(halomethyl)pyridine havingthe formula:

' XCHr- CH:X N wherein X represents a halogen atom, with a metalsalt oran amine salt of dithiocarbamic acid of the formula:

I R R NC s H (III) (2) Alternatively, the pyridine bis(dithiocarbamate)derivative can be prepared by reacting 2,6-bis'(halomethyl) pyridine ofthe formula:

XCH OH x N (11) wherein X represents a halogen atom, with carbonbisulfide and an amine having the formula:

(3) Another alternative route for providing pyridinebis(dithiocarbamate) derivatives is to react a 2,6-bis(mercaptomethyl)pyridine of the formula:

withan isothiocyanate of the formula:

I whereinvR represents a lower alkyl or a lower alkene of pyridinebis(dithiocarbamate) derivatives of thefors RRN S CHr- N/ CHQS (LINRIRIwherein R represents a lower alkyl group, a lower alkene group, or aphenyl group and R represents a hydrogen atom or a lower alkyl group orR and R taken together may form a heterocyclic ring with the nitrogenatom.

or a phenyl group. y

. In the'first reaction scheme, the metal salt oryamine saltofuthedithiocarbamic acid having the formula:

cm) asan'ynt-ennnn a 2,"6-bis (halo m'ethyl)pyridine of the R R NC s Hformula: 1

' A ;(II)

wherein X represents a halogen atom, in accordance with the reactionmechanism a whereiu Q+ represents a metal or an amine cation. 7

.Thissame type -of .S-alkylationxanbe carried-out di- R R NH (IV) andwith a halide Compound II, according to the reaction mechanism 1Compound II+2CS +4R R NH Compound I+2R R NH-HX In this reaction, it ispossible to convert up to 2 moles of the amine to any inorganic alkalisalt;(see Example 3). This latter modification is an advantageousalternative -The substituent group R in the Compound I may be a widevariety of alkyl or alkene groups, but preferably is methyl, ethyl,propyl, isopropyl, allyl, phenyl or-tolyl.

- because its eliminates the necessity of using dlthiOCaI-- bamate,which israther unstable.

The substituent group R includes preferably hydrogen,

be easily prepared by reacting 2 equivalents of an amine having FormulaIV with carbon bisulfide, as follows:

2R R NH+ CS [R R NC( :S) S]"[NH R R 1 In some instances, it may bedesirable to replace 1 equivalent of an amine with another base, such asan alkali hydroxide, ammonium hydroxide, or triethylamine. When 1equivalent of sodium hydroxide is used, a sodium salt of thedithiocarbamate will be prepared, as follows:

thiocarbamic acid, which are formed by substituting the dithiocarbamatecation with said metal ion, and to use these salts as S-alkylationreagents.

It is preferable to use an inert, neutral solvent, which It is. alsopossible to use Ag, Zn, Mn or-Pb salts of diis capable of dissolving thehalide (II) in the reaction of I the halide (II) with the metal salt oramine salt of dithiocarbamic acid (III). Suitable solvents includeacetone, dimethylformamide, ethyl acetate or a lower alcohol. The

reaction may be carried out in a two-phase system by dissolving thehalide in benzene and then using an aqueous solution of thedithiocarbamate.

The reaction usually goes to completion at about 0 C. within arelatively short period of time. Such lower by mixing 10.8 g. of carbonbisulfide with 14.3 g. of

temperatures are desirable to prevent decomposition of b thedithiocarbamate. Lower temperatures are also desirable to preventreaction of the halide (II) with the amine. "Similar areactionconditions may be used, even if the halide (II) is reacted directly withthe carbon bisulfide and the amine. The pyridine bis- (dithiocarbamate)deriva- I tives formed herein, is recoverable in the form of 'spar-'RNCS whereinR may be a lower al-kyl, lower alkene, or phenyl such asmethyl, ethyl, propyl, isopropyl, allyl, phenyl or tolyl. I

anti-hypertensive activity and anti-inflammatory activity.

This reaction can be effected in an inert organic solvent,

as a homogeneous system using such solvents as benzene, toluene,chlorobenzene, chloroform, methylene chloride, acetonitrile, orpyridine. The addition reaction of the isothiocyanate to the thiolgroups of 2,6-bis(mercaptomethyl)pyridine, can be easily carried outwithout a catalyst.

The reaction period can be shortened, however, by application of heat,conveniently by the use of a water bath. When the solvent is distilledfrom the reaction mixture, a compound of the Formula I can be obtainedat high yields.

The compound can be purified by recrystallization, or

, the hydrochloride thereof can be recovered in a suitable solvent.

' The pyridine bis(dithiocarbamate) derivatives of this invention havebeen shown to be effective in the treatment of circulatory disorderssuch as hypertension and also for the treatment of -mental disorderssuch as schizophrenia. The administration of this compound i.p. (25mg./kg.) reduced the blood pressure by 30% in spontaneously.hypertensive rats. The reduction of blood pressure continued for atleast 6 hours. The endogenous norepinephrine content in the adrenalgland following oral administration decreased 20% as compared to acontrol.

Having generally described the invention, a more complete understandingcan be attained by reference to certain specific examples which areprovided herein for purposes of illustration only and are not intendedto be construed as limiting unless otherwise specifically specified.

EXAMPLE 1 96.7%) of bis(N-methyldithiocarbamate) derivative having thefollowing formula, which is in a form of colorless needle-like crystals,and having a melting point of 116- 117' C. was obtained.

II II CHaNHC S CH: N CH:S CNHCHa Elementary analysis (C H N S).Calculated value (percent): C, 41.64; H, 4.77; N, 13.25; S, 40.35.Analyzed value (percent): C, 41.66; H, 4.75; N, 12.95; S, 40.53. Thehydrochloride of said compound had a melting point (decomposition) of177 C.

Triethylamine N-methyldithiocarbamate was prepared triethylamine whilestirring at 0 C. 16.5 ml. of 26% methylamine methanol solution wasadded, dropwise, to said mixture and then the precipitate wasrecrystallized from methanol-isopropyl ether to yield 17.3 g. ofcrystals having a melting point (decomposition) of 115 C. The acutetoxicity ofthe resulting bis(N-methyldithiocarbamate) derivative wasquite low, i.e., intraperitoneal LD of 1500 mg./kg. in mice.

The pharmacological tests evidenced quite significant When the compound(50 mg./kg.) was intraperitoneally injected to spontaneouslyhypertensive rats, a 30% reduction in blood pressure was observed. Thedose producing 50% fatalities in mice was higher than 3 mg./kg. Thedesirable effects of this drug was observable for up to 6 hours afteradministration.

EXAMPLE 2 1.7 g. of potassium N-rnethyldithiocarbamate was reacted with1.0 g. of 2,6-bis(chloromethyl)pyridine in acetone at 0-5 C. 1.64 g.(yield 92%) of the bis(N-meth'yldithiocarbamate) derivative, having theformula stated in Example 1, in crystal form and having a melting pointof 116-117 C. was obtained.

5 EXAMPLE 3 30 g. of 2,6-bis(chloromethyl)pyridine was dissolved in 250ml. of acetone and 30 g. of carbon bisulfide was added and cooled whilestirring. 15 g. of sodium hy droxide was dissolved in 50 ml. of waterand was admixed with 45 g. of a 30% methylamine aqueous solution atmoderately low temperatures.

The resulting solution was added, dropwise, to the first solution, whilecooling to maintain the temperature at 5 C., since the reaction wasexothermic. When the mixture was stirred for 1 hour at this temperature,a spot of the 2,6-bis(chloromethyDpyridine starting material disappearedduring thin layer chromatographic analysis.

500 ml. of water was added to the reaction mixture to precipitatecrystals. When the resulting product was recrystallized from methanol,52 g. (yield 96.5%) of bis(N-methyldithiocarbamate) derivative havingthe formula stated in Example 1 in the form of crystals having a meltingpoint of 116117 C. was obtained.

EXAMPLE 4 1.1 g. of sodium N-ethyldithiocarbamate was suspended in 10ml. of acetone and was reacted with 1.0 g. of 2,6-bis(chloromethyl)pyridine at 05 C. for 1 hour. The

resulting product had the following formula and was converted to thehydrochloride salt thereof to yield 1.36 g. of crystals having a meltingpoint of 137 C.

S I ll CgHsNHSCHz N CHzSCNHCzHn Elementary analysis (C H N S-HCl).-Calculated value (percent): C, 40.87; H, 5.28; N, 11.00; S,33.57; C], 9.28. Analyzed value (percent): C, 40.64; H, 5.09; N, 11.04;S, 33.35; Cl, 9.08.

EXAMPLE 5 Elementary analysis (C H N S ).-Calculated value (percent): C,48.25; H, 6.21; N, 11.26; S, 34.28. Analyzed value (percent): C, 48.19;H, 6.32; N, 11.39; S, 34.04.

The sodium N-isopropyldithiocarbamate was prepared by dissolving 3.45 g.of sodium hydroxide in 5 m1. of water and then adding 6.5 g. of carbonbisulfide after cooling and adding thereto, dropwise, a solution of 5 g.of isopropylamine in ml. of acetone. The mixture was reacted at roomtemperature for 1 hour, and was filtered and washed with acetone, toyield 13.3 g. (yield 100%) of crystals having a melting point(decomposition) of 138 C.

EXAMPLE 6 1.3 g. of potassium N-allyldithiocarbamate was suspended inacetone while stirring, and was reacted with 1.0 g. of2,6-bis(bromomethyl)pyridine at 0-5 C. for 1 hour. When the product wasrecrystallized from ethyl acetate-hexane, 1.24 g. (yield 96%) of acompound having the following formula, in the form of crystals having amelting point of 87 C. was obtained.

S II II CHatCHCHzNHC S CH2- N CH2S CNHCHzCH:CH2

Elementary analysis (C H N S ).-Calculated value (percent): C, 48.74; H,5.18; N, 11.37; S, 34.70. Analyzed value (percent): C, 48.59; H, 511; N,11.46; S, 34.65.

EXAMPLE 7 1.6 g. of ammonium N-phenylldithiocarbamate was reacted with10 g. of 2,6-bis(bromomethyl)pyridine in acetone at O-5 C. for 1 hour toattain S-alkylation. When the product was recrystallized from benzene,1.47 g. (yield 92%) of the compound of the following formula, in theform of colorless needle-like crystals having a melting point of 112.5C. was obtained.

EXAMPLE 8 2.2 g. of sodium N,N-dimethyldithiocarbamate was reacted with2.0 g. of 2,6-bis(bromomethyl)pyridine in acetone at 0-5 C. for 1 hourto attain S-alkylation. When the product was recrystallized from ethylacetate, 2.39 g. (yield 92% of a compound having the following formulain the form of colorless needle-like crystals, having a melting point ofISO-152 C. was obtained.

S S H H (CHahNC S CHrLN CH2S CN(GHs)z Elementary analysis (C H N S).Calculated value, (percent): C, 45.21; H, 5.55; N, 12.17; S, 37.07.Analyzed value (percent): C, 45.20; H, 5.52; N, 12.09; S, 37.13.

Sodium N,N-dimethy1dithiocarbamate was prepared by mixing 10 g. ofcarbon bisulfide and 5.25 g. sodium hydroxide conc. aqueous solutionwhile stirring and while cooling, 40% dimethylamine aqueous solution wasadded to the mixture to effect precipitation. 17 g. (yield 92%) of acompound having a melting point of 107-109 C. was obtained.

EXAMPLE 9 1.4 g. of sodium N,N-pentamethylenedithiocarbamate was reactedwith 1.0 g. of 2,6-bis(bromomethyl)pyridine in acetone at 0-5 C. for 1hour to achieve S-alkylation. When the product was recrystallized fromethyl acetate, 1.55 g. (yield 96.7%) of a compound having the fol lowingformula, in the form of colorless needle-like crystals, having a meltingpoint of 98-99 C. was obtained.

Elementary analysis (C H N S ).Calculated value (percent): C, 53.64; H,6.40; N, 9.88; S, 30.09. Analyzed value (percent): C, 53.57; H, 6.40; N,9.77; S, 2979.

7 Sodium N,N-pentamethylenedithiocarbamate was pre pared by dissolving5.25 g. of sodium hydroxide in 25 ml. of distilled water and 10 g. ofcarbon bisulfide was added after cooling. 11.2 g. of piperidine wasadded dropwise to the mixture to effect precipitation. 23.4 g. (yield97.5%) of a compound having a melting point (decomposition) of 275 C.was obtained.

EXAMPLE 10 Elementary analysis (C H N S ).Calculated value (percent): C,41.64; H, 4.77; N, 13.25; S, 40.35. Analyzed value (percent): C, 41.66;H, 4.75; N, 12.92; S, 40.53.

S S n m n CHaNHC S OH N CH2S CNHCH:

EXAMPLE 11 1 g. of 2,6-bis(mercaptomethyl)pyridine and 1.3 g. ofethylisothiocyanate were dissolved in ml. of benzene and heated for 4hours. The reaction mixture was concentrated under reduced pressure toyield 2.1 g. (yield 98%) pyridine dithiocarbamate of the followingformula in the form of a colorless liquid having a boiling point of120122 C./ 1 mm. Hg. When the distillate was cooled to below roomtemperature, the product was completely crystallized. When thehydrochloride of the resulting product was recrystallized from amethano-isopropyl ether mixture, colorless needle-like crystals having amelting point of 137 C. were obtained.

s s CzHaNH S CH2 N/ -CH2S JNHCzHa Elementary analysis (C H NS.,-HCl).--Calculated value (percent): C, 40.87; H, 5.28; N, 11.00; S,33.5; Cl, 9.28. Analyzed value (percent): C, 40.64; H, 5.09; N, 11.04;S, 33.35; Cl, 9.08.

EXAMPLE 12 s s OHgzCHOHzNHiiSCH N/ CHgSPJNHCH CEhCHz Elmentary analysis(C H N S ).Calculated value (percent): C, 48.25; H, 6.21; N, 11.26; S,34.28. Analyzed value (percent): C, 48.19; H, 6.32; N, 11.39; S, 34.04.

EXAMPLE 13 1 g. of 2,6-bis(mercaptomethyl)pyridine and 1.2 g. ofallylisothiocyanate were dissolved in 5 ml. of benzene and the mixturewas heated for 4 hours. When the solvent was distilled and the productwas recrystallized from an ethyl acetate-hexane mixture, 1.82 g. (yield96%) of pyridine dithiocarbamate derivative having the following formulain the form of needle-like crystals, having a melting point of 87 C. wasobtained.

CHzIOHCHaNH S CHz N/ CH2S INHCHZOHKJH,

Elementary analysis (C H N S ).-Calculated value (percent): C, 48.47; H,5.18; N, 11.37; S, 34.70. Analyzed value (percent): C, 48.59; H, 5.11;N, 11.46; S, 34.65.

EXAMPLE 14 0.4 g. of 2,6-bis(mercaptomethyl)pyridine and 0.8 g. ofphenylisothiocyanate were dissolved in 2 ml. of henzone and the mixturewas heated for 4 hours. When the solvent was distilled and the productwas recrystallized from benzene, 0.89 g. (yield 89.5%) of a pyridinedithiocarbamate derivative having the following formula in the form ofneedle-like crystals and having a melting point of 112 C. was obtained.

s s n I u Q-NHC s CH ems ONE-Q Elementary analysis (C H N S ).Calculatedvalue (percent): C, 57.11; H, 4.34; N, 9.51; S, 29.04. Analyzed value(percent): C, 57.06; H, 4.26; N, 9.60; S, 28.89.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modications can be madethereto without departing from the spirit or scope of the invention asset forth herein.

Accordingly, what is claimed and intended to be covered by LettersPatent is:

1. A process for preparing a pyridine bis(dithiocarbamate) derivativehaving the formula:

RRNiiSCH N/ OH2S( 5NR R wherein R represents a lower alkyl or loweralkene group or a phenyl group and R represents a hydrogen atom or alower alkyl group or R and R taken together form a piperidine ring withthe nitrogen atom, which comprises reacting 2,6-bis(ha1omethyl)pyridinewith carbon bisulfide and an amine.

2. The process for preparing a pyridine bis(dithiocarbamate) derivativeof claim 1 which comprises reacting 2,6-bis(halomethyl)pyridine of theformula:

x011. omx N wherein X represents a halogen atom, with carbon bisulfideand an amine of the formula:

R R NH wherein R and R are as defined above.

References Cited UNITED STATES PATENTS 3,290,319 12/1966 Partyka260-294.8 E 3,467,663 9/1969 Inoue et al 260-2943 E FOREIGN PATENTS9,784 5/1967 Japan 26029'4.8 E

ALAN L. ROTMAN, Primary Examiner U.S. Cl. X.R.

260294.8 E, 295 CA; 424263

